Effects of .ALPHA.- and .BETA.-adrenergic blockers on chlorpromazine-induced elevation of plasma glucose and cyclic AMP in fed mice.

Abstract

Abstract-The subcutaneous administration of chlorpromazine (CPZ) caused a dose response increase in plasma glucose and cyclic AMP levels in fed male mice. Hex amethonium abolished the elevation of both plasma glucose and cyclic AMP. Pro pranolol did not inhibit the elevation of plasma glucose but inhibited the increase of plasma cyclic AMP. In contrast, phentolamine and yohimbine completely suppressed the elevation of plasma glucose but not that of plasma cyclic AMP. These results indicate that the hyperglycemia due to CPZ was mediated through the stimulation of a-adrenoceptor and on the contrary CPZ increased plasma cyclic AMP through the stimulation of p-adrenoceptor and that the increase in plasma glucose induced by CPZ was independent of the activation of adenylate cyclase and the increased plasma cyclic AMP. In addition, in contrast to phentolamine and yohimbine, phenoxybenzamine was ineffective to prevent the hyperglycemia induced by CPZ. Moreover, a higher dose of dihydroergotamine was required to inhibit the hyperglycemia. Several mechanisms considered to be involved in CPZ-induced hyperglycemia.CPZ has been demonstrated to induce hyperglycemia in rats through the activation of a and/or (3-adrenergic receptors (2-6). Hyperglycemia due to CPZ was reported to be closely related the epinephrine release from adrenal medulla (2, 4-7). Moreover an impaired peripheral utilization of glucose (2, 4), a role of the central nervous system (8) and a cor relation between the hypothermia and the hyperglycemia induced by CPZ (2) were indicated to take part in the mechanism of CPZ action. Nevertheless the detailed mechanism of the CPZ action, particularly the participation of a and 13-adrenergic receptors has not been clearly demonstrated.We demonstrated that an administration of CPZ elevated plasma cyclic AMP levels through the stimulation of adrenergic mechanisms (9).Both catecholamines and glucagon are known to elevate plasma glucose, hepatic and plasma cyclic AMP. Glucagon increases the plasma glucose and cyclic AMP levels through the increase in hepatic cyclic AMP. On the other hand, the mechanism of catecholamine to induce hyperglycemia has not been conclusively defined. Some workers stated that (3-adrenergic receptor might be involved in the hyperglycemia (10-12), while others reported

Differential Effects of Various Typical and Atypical Antipsychotics on Plasma Glucose and Insulin Levels in the Mouse: Evidence for the Involvement of Sympathetic Regulation

“…The release of medullary epinephrine is controlled by sympathetic preganglionic (cholinergic) neurons and thus could be blocked by the ganglionic blocker hexamethonium. Our finding that pretreatment with hexamethonium completely inhibited the elevation of plasma glucose induced by either chlorpromazine or clozapine confirms and extends earlier data on the effects of combined chlorpromazine and hexamethonium administration in mice 12 and rats. 23 In the present studies, chlorpromazine-and clozapine-induced hyperglycemia in mice was also completely blocked by pretreatment with the a 2 adrenoceptor antagonist, yohimbine, suggesting that the hyperglycemic effect is due to increased sympathetic nervous system activity.…”

“…Acute hyperglycemic effects of antipsychotics have been demonstrated in preclinical animal models for chlorpromazine in mice 11,12 and rats 13 and for various atypical antipsychotics in mice. 14 In addition, a recent hyperinsulinemic, euglycemic clamp study in rats showed the rapid development of peripheral insulin resistance after acute clozapine and olanzapine administration.…”

Effect of chlorpromazine on insulin release in mice: comparison between in vivo and in vitro.

“…We recently reported that CPZ causes hyperglycemia and an increase in plasma cyclic AMP level in mice through stimulation of the sympathetic nervous system (2-4). CPZ-induced hyperglycemia and in creases in plasma cyclic AMP level were completely abolished by the treatment of mice with adrenalectomy or hexamethonium bromide, a ganglion blocker (2)(3)(4). This indicates that there is no possibility that CPZ can raise the plasma glucose and cyclic AMP level by decreasing the phosphodiesterase activity in the peripheral tissues or blood due to calmodulin antagonistic action.…”

Effects of methanolic extract of <i>Pausinystalia yohimbe</i> bark on blood glucose level in normal fasting rats

“…According to this effect, the higher doses of methanolic extract of P. yohimbe bark (40 and 80 mg/kg/mL) may facilitate glucagon secretion and thus lesser reduction in blood glucose level was obtained. It was reported that, yohimbine may cause gradual increases in glucagon secretion [28][29][30][31].…”